PROJECT SUMMARY (PROJECT 1, Project Leader: Pizzagalli, McLean Hospital) The premise of this P50 resubmission is that major depressive disorder (MDD) and anxiety disorders are characterized by negative biases in approach-avoidance behaviors due to dysregulation within (1) cortico- striatal-midbrain circuitry and (2) nociceptin/orphanin FQ peptide and the nociceptin receptor (NOPR). Project 1 will directly contribute to this goal by using functional magnetic resonance imaging (fMRI) while unmedicated individuals with current MDD or anxiety or individuals with past MDD perform an approach-avoidance decision- making task we adapted from non-human primates (Project 3). In Study 1.1, 56 unmedicated individuals with current MDD or anxiety disorders and 56 demographically matched healthy controls will perform the approach- avoidance fMRI task after receiving placebo or a NOPR antagonist (which increased approach-related behaviors in both rats and humans in preliminary studies). In Study 1.2, 48 unmedicated, remitted individuals with past MDD and 48 healthy controls will perform the approach-avoidance task both before and after a psychosocial stressor. Aim 1 will test the hypothesis that, relative to controls, patients will show aberrant task-related activations in the anterior cingulate cortex, dorsolateral prefrontal cortex and striatum, and that these abnormalities will differentially impact dynamic computational decision parameters. In Aim 2, we expect that, relative to placebo, NOPR antagonism will significantly increase approach-related striatal activation and corticostriatal connectivity and normalize avoidance-related pACC activation. Aim 3 will test the hypothesis that, from pre- to post-stress, remitted MDD individuals will show significantly decreased approach-related striatal activation and corticostriatal functional connectivity and dysregulated avoidance-related pACC activation relative to controls. In Aim 4, expect that abnormal pACC, DLPFC and NAc activation will predict changes in depression, anhedonia, anxiety, and suicidality as well as approach-avoidance behaviors in daily life (assessed using ecological momentary assessments). Using post-mortem assays, Aim 5 will test the hypothesis that the NOPR and its interactions with the dopaminergic system is altered in MDD within cortico-striatal-midbrain circuitry. Contribution to Overall Center Goals and Interactions with Other Center Components. Project 1 will test the hypotheses that (1) MDD and anxiety show dysregulation within a cortico-striatal-midbrain circuitry that will be targeted using recordings, stimulation and chemogenetic approaches in Projects 2-4 (Aim 1); (2) nociceptin receptor antagonism will normalize approach/avoidance behavior in MDD and anxiety (Aim 2), similar to non- human primate findings in Project 3 and rodent findings from Projects 3-4; (3) a psychosocial stressor will induce behavioral and neural shifts toward increased avoidance in remitted individuals with past MDD (Aim 3), similar to rodent and NHP findings in Projects 3-4; (4) behavioral and neural markers of approach/avoidance behaviors will predict disease course 12 months later (Aim 4); and (5) MDD will be characterized by NOP/NOPR disruptions within cortico-striatal-midbrain regions that will be causally tested in Projects 2-4 (Aim 5).